Epstein-Barr virus early antigen diffuse (EBV-EA/D)-directed immunoglobulin A antibodies in systemic lupus erythematosus patients.

OBJECTIVE: We sought to determine whether the serological response towards lytic cycle antigens of Epstein-Barr virus (EBV) is altered in systemic lupus erythematosus (SLE) patients. METHOD: We used enzyme-linked immunosorbent assay (ELISA) to investigate the prevalence of EBV early antigen diffuse (EBV-EA/D) antibodies in sera from 60 patients with SLE, 40 with scleroderma (SSc), 20 with primary Sjögren's syndrome (pSS), 20 with rheumatoid arthritis (RA), 20 healthy controls, and also subjects with various circulating autoantibodies. Samples from patients were obtained from clinics specialized within the diseases in Denmark and Sweden and samples from healthy controls were obtained from volunteers. RESULTS: A significant elevated titre of immunoglobulin (Ig)A, IgG, and IgM EBV-EA/D antibodies was found in SLE patients compared to healthy controls, a finding not explained by immunosuppressive treatment or disease activity. The largest difference was observed for IgA EBV-EA/D antibodies (p = 0.0013) with a seropositive rate of 58% in SLE patients and 0% in healthy controls. RA and SSc patients and individuals seropositive for anti-Scl-70 were additionally found to have elevated titres of IgA EBV-EA/D antibodies (40%, p = 0.014; 60%, p = 0.015; and 38.5%, p = 0.045, respectively). However, the titres were generally lower than in SLE patients. CONCLUSION: Our findings support an association between EBV and SLE. The elevated titre of EBV-EA/D-directed IgA antibodies found in SLE patients could suggest reactivation of EBV in epithelial cells or reinfection of epithelial cells after reactivation in B cells, indicating lack of control of the latent infection.

How should medication errors be defined? Development and test of a definition.

AIMS: Definitions of medication errors vary widely in the literature, and prevalence from 2-75% in part because of this lack of consensus. Thus, clarification of the concept is urgently needed. The objective was to develop a clear-cut definition of medication errors and specify relevant error types in the medication process. METHODS: Based on existing taxonomy and through a modified Delphi-process consensus of definition and error types were reached among Danish experts appointed by 13 healthcare organisations and the project group. The experts prioritised five definitions of medication errors and score the relevance of 76 error types. Based on explicit criteria, the project group settled non-consensus cases. RESULTS: The panel consisted of 12 physicians, seven pharmacists, and six nurses. Consensus was reached for the definition "An error in the stages of the medication process - ordering, dispensing, administering and monitoring the effect - causing harm or implying a risk of harming the patient". Moreover, consensus for 60 of 76 error types was achieved. Applied to a historic dataset the definition reduced the number of medication errors from 34% to 7%. CONCLUSIONS: Experts deemed a definition using harm or risk of harm as cut-off point as the most appropriate in Danish hospital settings. In addition, they agreed on a list of 60 error types covering the medication process. Interestingly, a substantial lower occurrence of medication errors was found when applied to historic data. The definition is in accordance with international taxonomy, thus is assumed to be applicable to modern healthcare settings abroad.

Electronic real-time surveillance for influenza-like illness: experience from the 2009 influenza A(H1N1) pandemic in Denmark.

To enhance surveillance for influenza-like illness (ILI)in Denmark, a year-round electronic reporting system was established in collaboration with the Danish medical on-call service (DMOS). In order to achieve real-time surveillance of ILI, a checkbox for ILI was inserted in the electronic health record and a system for daily transfer of data to the national surveillance centre was implemented. The weekly number of all consultations in DMOS was around 60,000, and activity of ILI peaked in week 46 of 2009 when 9.5% of 73,723 consultations were classified as ILI. The incidence of ILI reached a maximum on 16 November 2009 for individuals between five and 24 years of age, followed by peaks in children under five years, adults aged between 25 and 64 years and on 27 November in senior citizens(65 years old or older). In addition to the established influenza surveillance system, this novel system was useful because it was timelier than the sentinel surveillance system and allowed for a detailed situational analysis including subgroup analysis on a daily basis.

Patient safety incidents involving transdermal opioids: data from the Danish Patient Safety Database.

Background Transdermal opioids are widely used among elderly adults with chronic pain. However, transdermal patches may be involved in a significant proportion of opioid-related patient safety incidents, as the application process includes several subprocesses, each associated with an individual risk of error. Objective The aim was to obtain specific knowledge on patient safety incidents related to transdermal opioid treatment within both the primary care sector and the hospital sector in Denmark. Setting The study is descriptive with data provided by the Danish Patient Safety Database. Methods We manually retrieved all patient safety incidents concerning transdermal opioids reported for 2018 from (1) the hospital sector and (2) the primary care sector. Study data were collected and managed using REDCap electronic data capture tools. Main outcome measure The available information for each incident was sorted into the following categories: location, medication process, type of problem, outcome at time of reporting, and outcome classification. Results A total of 866 patient safety incidents involving transdermal opioids were reported to the Danish Patient Safety Database in 2018. No fatal incidents were present in the database. In 386 cases, the incidents were reported as harmful, and these 386 cases were analysed. Most reports came from the primary care sector (nursing home, home care or social housing). The majority of incidents were related to the administration of the patch in the medication process, and the most prevalent problem was the omission of doses. Conclusion This study has demonstrated that the administration of transdermal opioids is challenging and may cause harm, particularly in the primary care sector. To improve patient safety, optimized systems, including guidelines on drug management and the continuing education of healthcare personnel in transdermal opioid management, are necessary. These guidelines should preferably incorporate reminders and checklists, since the omission of doses was the most reported problem.

How are medication errors defined? A systematic literature review of definitions and characteristics.

OBJECTIVE: Multiplicity in terminology has been suggested as a possible explanation for the variation in the prevalence of medication errors. So far, few empirical studies have challenged this assertion. The objective of this review was, therefore, to describe the extent and characteristics of medication error definitions in hospitals and to consider the consequences for measuring the prevalence of medication errors. DATA SOURCES AND STUDY SELECTION: and data extraction Studies were searched for in PubMed, PsychINFO, Embase and CINAHL employing primary search terms such as 'medication errors' and 'adverse drug events'. Peer-reviewed articles containing these terms as primary end-points were included. Study country, year, aim, design, data-collection methods, sample-size, interventions and MAIN RESULT: were extracted. Result of data synthesis Forty-five of 203 relevant studies provided a generic definition of medication errors including 26 different forms of wordings. The studies conducted in nine countries represented a variety of clinical settings and the approach was mainly descriptive. Of utmost importance is the documented prevalence of medication errors, which ranged from 2 to 75% with no associations found between definitions and prevalence. CONCLUSION: Inconsistency in defining medication errors has been confirmed. It appears that definitions and methods of detection rather than being reproducible and reliable methods are subject to the individual researcher's preferences. Thus, application of a clear-cut definition, standardized terminology and reliable methods has the potential to greatly improve the quality and consistency of medication error reporting. Efforts to achieve a common accepted definition that defines the scope and content are therefore needed.

Serum eosinophil granule proteins predict asthma risk in allergic rhinitis.

BACKGROUND: Allergic rhinitis is a common disease, in which some patients will deteriorate or develop asthma. It is important to characterize these patients, thereby offering the possibility for prevention. This study evaluated eosinophil parameters as potential indicators of deteriorating allergic airway disease. METHODS: The subjects of the study included all patients who suffered seasonal allergic rhinitis and had participated in a study 6 years earlier, in which blood eosinophils, serum eosinophil cationic protein (ECP) serum eosinophil peroxidase (EPO), nasal lavage ECP and nasal lavage EPO levels were measured. Patients in the present study were interviewed on occurrence of rhinitis symptoms during the last season, rhinitis outside season, asthma-like symptoms and asthma diagnosis, and were skin-prick tested for common aeroallergens. Eosinophil parameters from the study 6 years earlier were then tested for the ability to predict occurrence of new allergies, worsening of rhinitis and occurrence of asthma. RESULTS: Forty-four patients participated in the study. In four patients seasonal rhinitis symptoms had deteriorated, 10 had experienced perennial rhinitis symptoms, 14 reported asthma-like symptoms and seven had been diagnosed with asthma. Thirteen had developed additional sensitization. Patients developing asthma-like symptoms compared with patients with no such symptoms had significantly higher serum ECP (16.7 microg/l vs 8.2 microg/l; P < or = 0.01) and serum EPO (17.9 microg/l vs 8.8 microg/l; P < or = 0.05). Results were similar, considering patients diagnosed with asthma. Blood eosinophils and nasal lavage parameters were not related to development of asthma and asthma-like symptoms. No eosinophil parameter was related to deterioration of rhinitis or additional sensitization. CONCLUSION: Serum ECP and EPO in patients with seasonal rhinitis demonstrated a high predictive ability for later development of asthma.

Contaminating viral sequences in high-throughput sequencing viromics: a linkage study of 700 sequencing libraries.

OBJECTIVES: Sample preparation for high-throughput sequencing (HTS) includes treatment with various laboratory components, potentially carrying viral nucleic acids, the extent of which has not been thoroughly investigated. Our aim was to systematically examine a diverse repertoire of laboratory components used to prepare samples for HTS in order to identify contaminating viral sequences. METHODS: A total of 322 samples of mainly human origin were analysed using eight protocols, applying a wide variety of laboratory components. Several samples (60% of human specimens) were processed using different protocols. In total, 712 sequencing libraries were investigated for viral sequence contamination. RESULTS: Among sequences showing similarity to viruses, 493 were significantly associated with the use of laboratory components. Each of these viral sequences had sporadic appearance, only being identified in a subset of the samples treated with the linked laboratory component, and some were not identified in the non-template control samples. Remarkably, more than 65% of all viral sequences identified were within viral clusters linked to the use of laboratory components. CONCLUSIONS: We show that high prevalence of contaminating viral sequences can be expected in HTS-based virome data and provide an extensive list of novel contaminating viral sequences that can be used for evaluation of viral findings in future virome and metagenome studies. Moreover, we show that detection can be problematic due to stochastic appearance and limited non-template controls. Although the exact origin of these viral sequences requires further research, our results support laboratory-component-linked viral sequence contamination of both biological and synthetic origin.

Detection and identification of Anaplasma phagocytophilum, Borrelia burgdorferi, and Rickettsia helvetica in Danish Ixodes ricinus ticks.

Borreliosis is an endemic infection in Denmark. Recent serosurveys have indicated that human anaplasmosis may be equally common. The aim of this study was to look for Anaplasma phagocytophilum and related pathogens in Ixodes ricinus ticks and estimate their prevalence, compared to Borrelia, using PCR. Ticks were collected from three locations in Denmark: Jutland, Funen, and Bornholm. Ticks from Jutland and Funen were analysed individually, ticks from Bornholm were analysed in pools of 20. A. phagocytophilum was found in ticks from all areas. A. phagocytophilum was found in 23.6% of ticks from Jutland and Funen, while 11% were positive for Borrelia burgdorferi. The Borrelia genotype B. afzelii was most prevalent, followed by B. valaisiana, B. burgdorferi s.s. and B. garinii.A. phagocytophilum was found in 14.5% of nymphs and 40.5% of adult ticks, while Borrelia was found in 13% of nymphs and 8% of adult ticks. The difference in prevalence between Anaplasma and Borrelia in adult ticks supports the idea that their maintenance cycles in nature may be different. Ticks were also infected with Rickettsia helvetica. Our study indicates that A. phagocytophilum prevalence in ticks in Denmark is as high as Borrelia prevalence and that human anaplasmosis may be unrecognized.

Intranasal corticosteroids for allergic rhinitis: superior relief?

Whether first-line pharmacological treatment of allergic rhinitis should be antihistamines or intranasal corticosteroids has been discussed for several years. First-generation antihistamines are rarely used in the treatment of allergic rhinitis, mainly because of sedative and anticholinergic adverse effects. On the basis of clinical evidence of efficacy, no second-generation antihistamine seems preferable to another. Similarly, comparisons of topical and oral antihistamines have been unable to demonstrate superior efficacy for one method of administration over the other. Current data documents no striking differences in efficacy and safety parameters between intranasal corticosteroids. When the efficacy of antihistamines and intranasal corticosteroids are compared in patients with allergic rhinitis, present data favours intranasal corticosteroids. Interestingly, data do not show antihistamines as superior for the treatment of conjunctivitis. Safety data from comparative studies in patients with allergic rhinitis do not indicate differences between antihistamines and intranasal corticosteroids. Combining antihistamines and intranasal corticosteroids in the treatment of allergic rhinitis does not provide any additional effect to intranasal corticosteroids alone. On the basis of current data, intranasal corticosteroids seem to offer superior relief in allergic rhinitis than antihistamines.

Respiratory tract infections in cytomegalovirus-excreting and nonexcreting infants.

BACKGROUND: There is evidence of an immunosuppressive effect of cytomegalovirus (CMV), and CMV has been claimed to be a copathogen in respiratory tract infections (RTI). We therefore studied the significance of CMV viral load in infants with RTI, compared the frequency of infection with respiratory viruses and followed the course of RTI in CMV-excreting vs. nonexcreting infants. METHODS: We examined 201 infants consecutively admitted to the Department of Pediatrics for RTI. At admission nasopharyngeal aspirates, throat swabs and urine were examined for CMV, and nasopharyngeal aspirates were examined for respiratory viruses. RESULTS: In these patients 23.3% had CMV in the urine, 15.3% had CMV in the throat and 10.9% had CMV in the nasopharynx; 26.2% excreted CMV in at least one site. No relationship was found between CMV viral load and clinical symptoms. Infection with respiratory viruses was as common in infants excreting CMV as in nonexcreting infants. Symptoms and the course of infection were not different in the two groups except that CMV-excreting infants had a significantly higher frequency of rhonchi at admission (P = 0.007) and a tendency for longer duration of cough (P = 0.06). CONCLUSION: CMV viral load was not related to clinical symptoms. The frequency of infection with common respiratory viruses in infants was independent of CMV excretion. The course of infection was not more complicated in infants excreting CMV; however, a higher frequency of rhonchi was demonstrated in patients with CMV.

No difference in enterotoxin production among Staphylococcus aureus strains isolated from blood compared with strains isolated from healthy carriers.

The production of enterotoxin A, B, C and D by 196 Staphylococcus aureus strains isolated from blood cultures and 95 strains from nasal carriers was investigated. Half of the bacteraemia strains were from patients who died with or because of their infection, the other half from patients who survived. The nasal strains were selected to match the bacteraemia strains regarding phage types. Overall, 30.6% of the bacteraemia strains and 40.0% of the nasal strains produced enterotoxins; enterotoxins B and C were the toxins produced most frequently in both groups. A similar incidence and pattern of enterotoxin production was found among the bacteraemia strains of S. aureus regardless of acquisition of the infection, the portal of entry, presence or absence of endocarditis and outcome of the infection. Thus, the concept that the enterotoxins play an important role in staphylococcal infections, apart from the diseases caused by the toxins per se such as food poisoning and toxic shock syndrome, cannot be substantiated by the results of the present study.

Effect of nasal inflammation and of intranasal anti-inflammatory treatment on bronchial asthma.

It is logical to look upon the nose and the bronchi as integrated parts of one 'united airway' and we would like to advance the hypothesis that optimal management of airway disease, caused by inhaled allergens, may necessitate control of inflammation in all parts of the airways. Nasal inflammation can aggravate asthma symptoms, and there is a rationale for giving intranasal anti-inflammatory treatment to patients with asthma. (i) Inhaled allergens are predominantly deposited in the nose, whether a patient suffers from rhinitis, asthma or both. (ii) Antigen presentation consequently takes place in the nose, and the response of the airway immune system is thus initiated in the nasal mucous membrane. (iii) Antigen presentation in the nose may possibly induce cell recruitment and activation not only in the nasal mucosa but also in the lower airways. (iv) Suppression of nasal inflammation may therefore be necessary for optimal management of asthma.

Regulated exocytosis in immune function: are SNARE-proteins involved?

Inflammation is an important feature in the pathogenesis of most chronic lung diseases. It is characterized by tissue infiltration with various inflammatory cells, including eosinophils, mast cells, basophils, macrophages, neutrophils, T- and B-lymphocytes and dendritic cells (1). In the tissue granulocytes release their toxic granule proteins after being stimulated by soluble mediators released by other inflammatory cells (2). Therefore, it is important to characterize the intracellular mechanisms regulating the transport of the granule contents in inflammatory cells. Intracellular vesicle-traffic in mammalian cells is mediated by transport vesicles that emerge from donor compartments and are specifically targeted to acceptor compartments where they deliver their contents after membrane fusion (3). This traffic leads to three types of fusion: vesicle-intracellular membranes, vesicle-vesicle or vesicle-plasma membrane. The process leading to fusion of vesicle-plasma membrane is called exocytosis, and it delivers proteins to the cell surface (receptors e.g. CD11b, CD18) and exports soluble molecules (mediators e.g. ECP) from the cell. A number of key proteins involved in regulated exocytosis have been identified from inflammatory cells. This review is a brief summary of these proteins and it includes recent results from studies on regulated exocytosis in inflammatory cells.

Salmeterol reduces the need for inhaled corticosteroid in steroid-dependent asthmatics.

Previous results have demonstrated addition of long-acting beta2-adrenergic agonists to be beneficial in asthma patients already receiving inhaled corticosteroid. The purpose of this study was to determine, qualitatively as well as quantitatively, the steroid-sparing properties of salmeterol in stable asthma patients receiving maintenance inhaled corticosteroids (800-1600 microg day(-1)). In these patients, the daily dose of beclomethasone dipropionate was reduced by 200 microg each week until asthma deteriorated, with the minimal acceptable dose (MAD) being defined as the dose one step above deterioration (sensitivity period). Following this, patients received three times the MAD for 2 weeks. Patients were randomized to receive either salmeterol 50 microg twice daily or placebo and the MAD was again determined (treatment period). Forced expiratory volume in 1 sec (FEV1) was measured each week. Morning and evening peak expiratory flow (PEF), symptom score and use of bronchodilator were recorded each day. Fifteen patients received salmeterol and 19 placebo. The MAD was significantly lower in the salmeterol group compared with placebo during the treatment period (P<0.01). A 50% reduction of the MAD was achieved by more patients treated with salmeterol than placebo (P = 0.001). Salmeterol caused a significantly greater reduction in daytime symptom score and use of as-needed beta2-agoinist therapy between sensitivity and treatment periods compared with placebo (P<0.05 for both). The results demonstrate, that the addition of salmeterol to corticosteroid treatment offers a clinically relevant potential for reduction of inhaled corticosteroid dose in steroid sensitive asthmatics.

Human blood eosinophils produce and secrete interleukin 4.

Interleukin 4 (Il-4) is an immunoregulatory cytokine which induces T-cell proliferation and differentiation into a Th2 phenotype, and is of particular importance for the induction of IgE synthesis. In the present study, the capability of human peripheral blood eosinophils from allergic and non-allergic donors to produce Il-4 was examined. Using reverse transcribed polymerase chain reaction (RT-PCR), it was shown that highly purified eosinophils from allergic patients express mRNA for Il-4. Resting eosinophils also gave specific immunoreactivity with anti-Il-4 antibodies, consistent with translation of Il-4 mRNA. Light and electron microscopic immunocytochemistry revealed that Il-4 was prestored in the eosinophilic granules. These results were confirmed by Il-4 specific ELISA which showed that Il-4 production could be upregulated in the eosinophils and released from the eosinophils following stimulation with the calcium ionophore A23187. These data indicate that eosinophils may be an important source of Il-4 at sites of allergic inflammation. Thus, eosinophils may act as immunomodulatory cells enhancing the allergic response through formation of Th2-cells and inducing the isotype switching to IgE in human B-cells.

Phylogenetic relationships of a large marine Beggiatoa.

Based upon 16S rRNA sequence and phenotypic similarities, a large, uncultured Beggiatoa sp. from the Bay of Concepción (Chile), is very closely related to the Chilean Thioploca species Thioploca araucae., whose filaments grow as sheathed bundles. The formation of sheathed filament bundles, the key character to distinguish the genus Thioploca from Beggiatoa, places closely related filamentous sulfur-oxidizing bacteria into two different genera, incongruent with 16S rRNA-defined clades.

Methane microprofiles in a sewage biofilm determined with a microscale biosensor.

Microprofiles of the methane concentration in a 3.5-mm-thick sewage outlet biofilm were measured at high spatial and temporal resolution using a microscale biosensor for methane. In the freshly collected biofilm, methane was building up to a concentration of 175 mumol l-1 at 3 mm depth with a total methanogenesis of 0.14 mumol m-2 s-1, as compared to an aerobic respiration (including methane oxidation) of 0.80 mumol m-2 s-1. A model biofilm was established by homogenisation of an in situ biofilm and 12 days of incubation with surplus sodium acetate. The homogenised biofilm was able to maintain 50% of the methanogenic activity in the absence of external electron donor. Oxygen had only a minor effect on the methane production, but aerobic respiration consumed a substantial part of the produced methane and was thus an important control on methane export from the biofilm. A concentration of 2 mmol l-1 nitrate was shown to inhibit methanogenesis only in the upper layer of the biofilm, whereas a further addition of 2 mmol l-1 sulphate inhibited methanogenesis in the entire biofilm. The study demonstrated the power of the methane microsensor in the study of microhabitats with concurrent production and consumption of methane.

Pathways of organic carbon oxidation in three continental margin sediments.

We have combined several different methodologies to quantify rates of organic carbon mineralization by the various electron acceptors in sediments from the coast of Denmark and Norway. Rates of NH4+ and Sigma CO2 liberation sediment incubations were used with O2 penetration depths to conclude that O2 respiration accounted for only between 3.6-17.4% of the total organic carbon oxidation. Dentrification was limited to a narrow zone just below the depth of O2 penetration, and was not a major carbon oxidation pathway. The processes of Fe reduction, Mn reduction and sulfate reduction dominated organic carbon mineralization, but their relative significance varied depending on the sediment. Where high concentrations of Mn-oxide were found (3-4 wt% Mn), only Mn reduction occurred. With lower Mn oxide concentrations more typical of coastal sediments, Fe reduction and sulfate reduction were most important and of a similar magnitude. Overall, most of the measured O2 flux into the sediment was used to oxidized reduced inorganic species and not organic carbon. We suspect that the importance of O2 respiration in many coastal sediments has been overestimated, whereas metal oxide reduction (both Fe and Mn reduction) has probably been well underestimated.

The role of type II collagen autoimmunity in otosclerosis revisited.

A recent theory, suggesting that otosclerosis results from autoreactivity to type II collagen present in the fetal cartilaginous remnants of the human bony labyrinth, is based on two observations. Otosclerotic patients have increased concentrations of circulating antibody to type II collagen, and immunization of rodents with cartilage collagen induces 'otosclerosis-like' lesions. Independent researchers have been unable to confirm the first promising results. No significant abnormalities could be found in immunized animals. We report the result of type II collagen antibody recordings in a well described group of otosclerotic patients and controls, and the histological findings in temporal bones of MRL/1-mice with spontaneous type II collagen autoreactivity. Our results cannot support the view of autoreactivity to type II collagen as an etiopathogenetic factor in otosclerosis.